Novel substituted 21-nor-delta20(22), 23-steroidal dienes



United States Patent This invention relates to new steroid compounds.More particularly, A -steroidal dienes and to methods for theirpreparation.

The novel compounds of this invention may be represented by thefollowing formula:

wherein X is selected from the group consisting of hydrogen, loweralkyl, carbo loweralkoxy and cyano; Y is selected from the groupconsisting of carbo loweralkoxy, cyano and nitro; R is lower alkyl; R isselected from the group consisting of hydrogen and lower alkanoyl and (30 isa trivalent radical selected from the group consisting of a. 50s andi v a 1'1 CH2 The novel compounds of the present invention are ingeneral crystalline solids substantially insoluble in water and somewhatsoluble in the usually available organic solvents. r

The compounds of this invention are prepared from the steroids describedin our US. Patent 3,201,425. These starting materials have the structurehereinbefore described with the exception that the 21-p0sition containsa formyl group. To produce the present compounds, the 2l-formyl steroidsare reacted with various reagents such as, for example,triethylphosphonoacetate, ethylbromoacetate zinc,carbethoxyethylidenetriphenylphosphone, dimethyl malonate, diethylcyanomethylphosphonate, malononitrile, ethyl cyanoacetate, nitromethane,nitroethane and the like.

The process of the present invention is preferably carried out in asolvent at a temperature of from about 25 C. to 150 C. for a period offrom 10 minutes to 10 hours. The solvents may be for example;tetrahydrofuran, benzene, absolute ethanol, nitrornethane, nitroethaneand the like. The reagent to produce the desired compound when reactedwith the 21-formylsteroidmay, when liquid, also serve as the solvent forthe reaction.

Among the 21-formylsteroids useful as starting materials in the processof the present invention may be, for example, I

it relates to novel substituted 21-norice3,8-acetoxy-20-ethoxy-21-formylpregna-5,20-diene,

21-formyl-3,8,ZO-dimethoxypregna-5,20-diene,

3,8-acetoxy-21-iforrnyl-20-methoxy-16a-methylpregna- 5,20-diene,

3 fl-acetoxy-20-ethoxy-2 l -formyll 6u-methylpregna- 5,20-diene,

3 fi-acetoxy-Z 1-formyl-20-rnethoxyallopregn-ZO-ene,

3 fl-acetoxy-Z 1 -formyl-20-methoxypregn-20-ene,

3 fl-acetoxy-Z 1-formyl-20-methoxy-6-rnethylpregna-5,20-

diene,

3 a,6a-diacetoxy-2 1 -formyl20-methoxypregn-20-ene,

3 a,12a-diacetoxy-21-formyl-20-methoxypregn-ZO-ene,

21-formyl-3 ,3 ,20-trirnethoXypregna-1 1,20-diene,

21-formyl-20-Inethoxypregna-S,ZO-dien-Sfi-ol,

and 20-ethoxy-2 l -formypregna-5,20-dien-35-01.

The novel compounds of the present: invention possess antigonadotropicand anabolic activity when administered to warm-blooded animals. Assuch, therefore, the com pounds have utility as therapeutic agents,particularly in protein replacement therapy.

The invention will be described in greater detail in conjunction withthe following specific examples describing the preparation ofrepresentative 21nor-A steroidal dienes.

EXAMPLE 1 Preparation of ethyl 3p-acet0xy-20-naeth0xy-21more/rela- 5,2O-[cis] ,23 trans] -trien e-24-carb0xylate This compound may be preparedby either of two following procedures.

Procedure A.Triethylphosphonoacetate (1.13 g.) is dissolved in drytetrahydrofuran (50 ml.) and stirred for 1 hour, after the addition of0.22 g. of sodium hydride (54.7% oil suspension). To this mixture isadded a solution of 1.0 of 3fl-acetoxy-2l-formyl-ZO-methoxypregna5,20-(22) -diene in 10 ml. of dry tet-rahydrofuran. This reactionmixture is stirred for 1 hour and then refluxed for hour. The solvent isremoved at reduced pressure, water is added and the mixture is extractedwith ether. The ether extract is washed well with a saturated salinesolution, dried and evaporated to yield a solid. The solid isrecrystallized twice from methanol to yield 0.52 g. of ethyl3B-acetoxy-Ztl-methoxy-Zl-norchola-5,20[cis] ,23[trans]-triene-24-carboxylate, melting point 161162 C., i

M .on Mix.

Procedure B.Zinc dust 1.64 g.) is suspended in benzene (100 ml.) and thereaction mixture distilled until ml. of benzene is collected. To thisdried solution, ethyl bromoacetate (4.17 g.) in dry benzene (25 ml.) isadded and the mixture is refluxed for 1 hour. After the zinc reagent hasbeen prepared 2.0 g. of 3/3-acetoxy-21-forrnyl-20-methoxypregna-5,20-diene in 25 ml. of dry benzene is addedand refluxing is continued for 1 hour. Water is added to decomposeexcess reagent and then 20% aqueous sulfuric acid is added. The reactionmixture is extracted with other which in turn is washed with saturatedsodium bicarbonate and then with a saturated saline solution.Evaporation of the ether gives a solid which is subsequentlychromatographed on activated magnesium silicate. The material elutedwith the latter 2% acetonepetroleum ether (1x100 ml.) and the initial 3%acetone-petroleum ether (4X ml.) fractions is recrystallized frommethanol to yield 0.46 g. of the subject cornpound, melting point -156C.

3 EXAMPLE 2 Preparation of ethyl 3/3 acetoxy 20-eth0xy-244nethyl -21-nrchola-5,20 [leis] ,23- [trans] -triene-24-earb0xylate A solution of3,6-acetoxy-20-ethoXy-2l-formylpregna-S, 20-diene (2.0 g.) in benzene(100 ml.) is distilled until 50 ml. of benzene is collected. To thisdried reaction mixture is added carbethoxyethylidenetriphenylphosphone(5.14 g.) and this is refluxed for 6 hours under nitrogen. Thin layerchromatography of the crude reaction mixture indicates approximately 50%conversion of the aldehyde into the dienic ester. Chromatography onactivated magnesium silicate with elution with 2 and 3% acetone-hexanemixtures and recrystallization from methanol-water and methanol gives0.93 g. of ethyl 3B-acetoxy-20-ethoxy- 24methyl-21-norchola-5,20[cis],23-[trans] triene-24- carboxylate, melting point 128-132 C.,

NYSE 303 n (e 25,700)

EXAMPLE 3 Preparation of dimethyl3B-acet0xy-20-methoxy-21-norchow-5,20[cis],23-triene-24,24-diearb0xylateA reaction mixture consisting of 3,8-acetoxy-21-formyl-20-methoxypregna-5,20-diene (2.0 g.) acetic anhydride (20 ml.), dimethylmalonate (0.8 m1.) and zinc chloride (50 mg.) is refluxed for 1 hour.After cooling, the solution is poured into water and the mixture isfiltered. A methylene chloride solution of the crude solid is passedthrough a hydrous magnesium silicate pad and eluted with additionalmethylene chloride (400 ml.). Evaporation of the eluate yields acrystalline solid which is further chromatographed on activatedmagnesium silicate. The material eluted with the latter 4%acetone-petroleum ether (2x100 m1.) and early 6% acetone-petroleum ether(4x100 ml.) fractions is combined and recrystallized from acetone-hexaneto yield 0.98 g. of the diester, dimethyl 3 8acetoxy-20-methoxy-21-n0rchola-5,20-[cis],23-triene-24,24-dicarboxylate, melting point 167170 C.,

max-

This compound is useful for its antigonadotropic activity.

EXAMPLE 4 Preparation of dimethyl 3l3-aeet0xy-20-eth0xy-21-n0r-Ch0ld-5,20 [cis] ,23- [trans] -triene 3fi-acetoxy-20-ethoxy 21formylpregna 5,20-diene (0.83 g.) and dimethyl malonate (0.29 g.) aredissolved in 50 ml. of absolute ethanol containing 0.17 ml. ofpiperidine and two drops of glacial acetic acid. After refluxing on asteam bath for 0.5 hour the reaction mixture is evaporated to drynessyielding a yellow gum (0.40 g.) which crystallizes on the addition ofmethanol. Two recrystallizations from methanol gives the whitecrystalline product, dimethyl 3/3 acetoxy 20-ethoxy-21-norchola-5,L20[cis],23-triene-24,24-dicarboxylate, melting point 120 122 C.,

EXAMPLE Preparation of 3/3 aeetoxy-Z 4 -cyan0-2 O-methoxy -21-norchalet-5,20 [cis] ,23- [trans] -triene oration of the ether gives asolid which is crystallized from methanol (activated carbon used toremove impurities) to yield 2.2 g. of3,8-acetoxy-24-cyano-20-methoxy-21-norchola 5,20[cis],23-[trans] triene,melting point 209-212 C. Recrystallization from methanol gives 1.2 g. ofan analytical sample, melting point 219220 C.,

Preparation of 313 acetoxy-24,24-dicyan0-20-ethoxy-ZI-n0rch0la5,20[Cis],23-triene EXAMPLE 7 Preparation of ethyl 3,8acetoxy-24-cyano-20-ethoay-ZI- n0rch0la-5,20 [01's] ,23- [trans]-triene-24-carb0xy llate A reaction mixture consisting of 36-acetoxy-20-ethoxy- 2l'fOrmyl regna-SQO-diene (1.0 g.), ethylcyanoacetate (0.3 ml.), piperidine (0.2 ml.), and two drops of glacialacetic acid in 50 ml. of absolute ethanol is refluxed for 5 minutes andcooled. The precipitated solid (0.94 g.) melting point 17l-172 C. iscrystallized from methanol to yield 0.76 g. of ethyl3B-acetoxy-24-cyano-20-ethoxy- 21-norchola5,20[cis],23-[trans]-triene-24 carboxylate with no change in meltingpoint,

EXAMPLE 8 Preparation 0 3(3 acet0xy-20-meth0xy-24-nitr0-21-n0rchola-5,20efs] ,23- trans] -triene 3,8 acetoxy-21-formyl-20-methoxypregna5,20-diene (1.0 g.) ammonium acetate (0.5 g.) in nitromethane (10 ml.)is heated on a steam bath for 0.5 hour and then poured into water. Theprecipitated solid is filtered off, dissolved in methylene chloride andpassed through hydrous magnesium silicate. The orange-colored eluate iscollected, evaporated and crystallized to yield 0.225 g. of the nitrodiene, melting point 224-226 C.,

AMeOH max.

225 and 362 ni (6 7,500 and 18,000, respectively) This compoundpossesses anabolic activity.

EXAMPLE 9 Preparation of 3,8acetoxy-ZO-meth0xy-24-methyl-24-nitr0-21-n0rch0la-5,20 [01's] ,23-[trans] -triene Using the procedure of Example 8 and replacingnitromethane with 10 ml. of nitroethane, 0.32 g. of the yellow nitrotriene product is prepared, melting point 220- 221 C.,

Ami? 225 and 370 m (e 10,600 and 14,400, respectively) EXAMPLE l0Prepara lion 0 f 3 3 acetoxy-Z 0-methoxy-24-nitr0-21 -n0r- 5a-ch0la-20[cis] ,23- [trans] -diene A suspnsion of 3,3 actoxy-21-formyl 20methoxypregn-ZO-ene (4.0 g.) and ammonium acetate (2.0 g.) innitromethane (50 ml.) is heated on a steam bath for 0.5 hour. Aftercooling the reaction mixture is poured into water and separated into aliquid and semisolid phase. The semisolid is dissolved in methylenechloride and passed through a hydrous magnesium silicate pad. 400 ml. of.additional methylene chloride is passed through the pad. Evaporation ofthe eluate gives a red-orange colored solid which is recrystallizedthree times from methanol to yield 0.37 g. of the nitroolefin, meltingpoint 183-184 C.,

AMBOH 252 and 362 mu (6 7,150 and 10,000, respectively) max.

What is claimed is: 1. A steroid of the formula:

2. A compound according to claim 1, wherein the steroid is ethyl3fi-acetoxy-20-methoxy-21-norchola-5,20- [cis] ,23- [trans]-triene-24-carboxylate.

3. A compound according to claim 1, wherein the steroid is ethyl3,8-acetoxy-20-ethoxy-24-rnethyl-21-norchola-5,20[cis],23-[trans]-triene-24-carboxylate.

4. A compound according to claim 1, wherein the steroid is dimethyl3B-acetoxy-20-methoxy-2l-norchola-5,20[cis],23-triene-24-24-dicarboxy1ate.

5. A compound according to claim ll, wherein the steroid is dimethyl3B-acetoxy-20-ethoxy-21-norchola-5,20-[cis],23-triene-24,24-dicarboxylate.

6. A compound according to claim ll, wherein the steroid isacetoxy-24-cyano-20-methoxy-2l-norchola-S, 2O [cis] ,23 [trans] -triene.

7. A compound according to claim ll, wherein the steroid is 3 ,8acetoxy-24,24-dicyano-20-etl1oxy-2l-norchola- 5,20[cis]-23-triene.

8. A compound according to claim I, wherein the steroid is ethyl3,8-acetoxy-24-cyano-20-etl1oxy-2l-norchola- 5 ,20 [cis] 23 [trans]-triene-24-carboxylate.

9. A compound according to claim 1, wherein the steroid is3fl-acetoxy-Z0-meth0Xy-24-rnethyl-24-nitro-2l-norchola-5,20[cis],23-[trans]-triene.

10. A compound according to claim 1, wherein the steroid is3fl-acetoXy-20-methoxy-24-nitro-2l-nor-ia-chola-20[cis],23-[trans]-diene.

References Cited UNITED STATES PATENTS 3,201,425 8/1965 Dusza et a1.260397.1

ELBERT L. ROBERTS, Primary Examiner.

1. A STEROID OF THE FORMULA: